Pharmacology of central Neurotransmitters Prof. Yieldez Bassiouni Dr. Ishfaq Bukhari

Objectives The main objective of this lecture is to understand the role of neurotransmitters in the etiology and treatment of CNS diseases

A membrane action potential arriving at the terminal opens axonal Ca channels; Ca inflow releases neurotransmitter molecules from many vesicles by fusing the vesicle membranes to the nerve terminal membrane. Membrane fusion generates an opening through which the molecules are expelled into the synaptic cleft via exocytosis

Neurotransmitters Endogenous chemicals or chemical messengers that enable neuro-transmission (transmit signals from a neuron to a target cell across a synapse). They packed into synaptic vesicles under the membrane in the axon terminal, on the presynaptic side. They are released into & diffuse across the synaptic cleft to bind to a specific receptors on the post synaptic side.

- The neurotransmitter-receptor interaction must be terminated quickly to allow rapid, repeated activation of receptors. One of the following can happen to neurotransmitters that have interacted with receptors: 1- They can be quickly pumped back into the presynaptic nerve terminals by active, ATP-dependent processes (reuptake) Neurotransmitters taken up by the nerve terminals are repackaged in vesicles for reuse. 2- They can be destroyed by enzymes near the receptors. 3- They can diffuse into the surrounding area and be removed.

Neuropsychopharmacological science seeks to : Understand how drugs can affect the CNS selectively to relieve pain, improve attention, induce sleep, reduce appetite, suppress disordered movements ….ect. To provide the means to develop appropriate drugs to correct pathophysiological events in the abnormal CNS.

Examples of neurotransmitters Amino acids: Glutamate (Glu), gamma aminobutryic acid (GABA) Monoamines & other biogenic amines: Dopamine (DA), Norepinephrine (NE), Serotonin (5-HT) Peptides: Somatostatin Others: Acetylcholine (Ach) Somatostatin:a peptide hormone that regulates the endocrine system 

What is the importance of understanding neurotransmitters To understand the etiology of diseases To suggest the best drugs to be used To understand the other clinical uses of any particular drug

Norepinephrine ( NE)  

also called noradrenaline , belongs to catecholamines, the direct precursor of NE is dopamine The CNS effects of NE are manifested in alertness, arousal , and readiness for action. A variety of medically important drugs work by altering the actions of NE e.g., for treatment of CV problems and some of psychiatric conditions.

Mood disorders and NE Affective Disorders Mania Depression NE NE Rx Drugs that decrease NE Drugs that increase NE

Serotonin (5-HT)

Serotonin ( 5HT) 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter found in the CNS, GIT, platelets a contributor to feelings of well-being & happiness. Serotonin plays an important role in the regulation of mood, sleep; appetite, pain perception and some cognitive functions, including memory and learning.  Modulation of serotonin at synapses is a major action of several classes of antidepressants eg selective serotonin re-uptake inhibitors (SSRIs).

Diseases that are influenced by changes in 5-HT brain content: Depression Social phobia Obsessive Compulsive Disorders (OCDs) Generalized Anxiety Schizophrenia Vomiting

Dopamine Controls movements

Dopamine Pathways Controls movements Overactivity produces delusions

What are the diseases that influenced by dopamine level ? Attention deficit hyperactivity disorder (ADHD) Schizophrenia Depression Drug addiction Parkinson's disease

Acetylcholine

Acetylcholine (Ach), the first neurotransmitter discovered Inside the brain Ach functions as a neuro-modulator—a chemical that alters the way other brain structures process information rather than a chemical used to transmit information from point to point Is Ach an inhibitory or excitatory neurotransmitter?

Role of Acetylcholine in the CNS Ach is thought to be involved in cognitive functions such as : Memory Arousal Attention Memory Arousal الإثارة Attention انتباه

What are the CNS diseases that linked to ACH derangement ? Damage to cholinergic receptors ( muscarinic) is associated with memory deficits as in Alzheimer's disease. Muscarinic antagonists as hyoscine cause amnesia (Cholinomimetics are used as therapy of Alzheimer ). Increased brain level of Ach predispose to Parkinson's disease (anticholinergic drugs are used as therapy) Depression may be a manifestation of a central cholinergic predominance.

Glutamic acid - is an excitatory neurotransmitter - An increase in its level predispose to epilepsy

Potential therapeutic effect of glutamate antagonists Reduction of brain damage following strokes & head injury Treatment of epilepsy Drug dependence Schizophrenia

Gamma amino butyric acid “GABA” GABA is the main inhibitory neurotransmitter in the brain Present throughout the brain; there is very little in peripheral tissues

Pathophysiological role of GABA Decrease GABA brain content is associated with : Epilepsy Anxiety Convulsions Insomnia Benzodiazepine (diazepam) enhances GABA function and used in treatment of above diseases.

Conclusion: Without understanding the involvement of neurotransmitters in the etiology of CNS diseases, doctors could not select the proper drug for any particular disease.

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